This proposal focuses on biological markers in cerebrospinal fluid (CSF) related to Alzheimer's Disease (AD). Biomarkers that are clearly related to the pathology of AD, namely A-beta42 (the major protein in plaques) and tau (found in tangles) can discriminate patients with AD from controls. Less is known about these and other biomarkers in mild cognitive impairment (MCI), which is often a prodromal stage of mild AD, and in relation to aging and to genetic and other risk factors for AD. In this proposal, 4 AD Research Centers will collaborate to obtain CSF and plasma samples from well-characterized subjects with AD, MCI and healthy controls spanning the age range 20-80. About 50% of subjects will contribute a set of serial CSF and plasma samples at 12 month follow-up. This project builds on an existing collaborative CSF and plasma bank, and aims to accrue and bank samples from over 500 subjects. A-beta processing, production, deposition and clearance are important factors in AD. These will be investigated by measuring levels of species of A-beta (A-beta 38, 40 and 42) and of secreted, cleaved forms of beta-amyloid precursor protein (APP), the parent molecule of A-beta, in CSF. Indices of neurodegeneration and tangle formation will be studied by quantifying CSF levels of tau and phospho-tau, and tau will be purified from CSF and sequenced. As indices of oxidative damage and inflammation, mechanisms implicated in neuronal damage in AD, biomarkers such as F-2 isoprostanes, S100B and alpha1ACT will be measured. The relationship between these biomarkers and age, sex, diagnosis (normal, MCI, mild AD), degree of cognitive impairment, and genetic risk factors for AD (apolipoprotein E [ApoE] and CYP46 genotypes) will be examined, and the extent of change in biomarkers over 12 months will be analyzed. Banked CSF and plasma will be available for further research into novel biomarkers, including broad-based proteomic studies.